1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2009.11.099

A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRβ binding IC₅₀ values <10 nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.

Full text of DOI:10.1016/j.bmcl.2009.11.099

Bioorganic & Medicinal Chemistry Letters 20 (2010) 526–530
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists
a
b
b
Jeremy M. Travins a, , Ronald C. Bernotas a, , David H. Kaufman , Elaine Quinet , Ponnal Nambi ,
*
Irene Feingold c, Christine Huselton c, Anna Wilhelmsson d, Annika Goos-Nilsson d, Jay Wrobel a
a Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
b Cardiovascular and Metabolic Diseases, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
c Drug Safety and Metabolism, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
d Karo Bio AB, Novum S-141, 57 Huddinge, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High
affinity LXR ligands were identified (LXRb binding IC50 values <10 nM), some with excellent agonist
potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human
macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had
good oral exposure in mice.
Received 14 October 2009
Revised 17 November 2009
Accepted 19 November 2009
Available online 23 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Sulfone
ABCA1
LXR
Liver X receptor
Cholesterol
Lipid
Atherosclerosis
Nuclear receptors are a superfamily of receptors which regulate
gene expression. Among these gene transcription factors are the li-
Several structurally diverse LXR agonist series have been re-
ported. Among the earliest potent agonists for LXRa and LXRb were
ver X receptors (LXRs) comprised of two subtypes: LXR
a
and
Tularik’s T0901317 (1)7 and GlaxoSmithKline’s GW3965 (2)8
(Fig. 1). An indazole LXR agonist from Wyeth, LXR-623 (3),9 ad-
vanced to the clinic but had CNS effects at higher doses in phase I.10
LXRb.1 The highest level of LXR
a
is found in the liver but it is also
found in intestine, lung, kidney, spleen, and macrophages while the
LXRb subtype is expressed in nearly all cell types. Both subtypes
form heterodimers with retinoid X receptors (RXRs) and this
dimerization is required for activity.2 The heterodimer is activated
by binding either an RXR agonist (e.g., 9-cis-retinoic acid) or an LXR
agonist (e.g., endogenous oxysterols such as 24,25-epoxycholester-
ol).3 Activation causes expression of genes coding for several ATP-
binding cassette proteins (ABCs) which are responsible for lipid ef-
flux from cells.4 Among the more important ABCs are ABCA1, a key
lipid transporter in macrophages, and ABCG5 which is localized on
the intestinal wall and may reduce cholesterol absorption. Besides
their function in lipid efflux, LXRs have an anti-inflammatory role
so it has been proposed that LXR agonists may help prevent or re-
verse atherosclerosis through these two mechanisms.3,5 These
activities have made LXR agonists a pharmaceutical target.6
Ph
Ph
N
F3C CF3
HO
CO2H
O
O
O
S
N
Cl
F3C
CF3
1 T0901317 (Tularik)
2 GW3965 (GSK)
F
CO2H
O
N
Cl
N
N
CF3
CF3
* Corresponding author.
F
4 WAY-254011
E-mail address: bernotr@wyeth.com (R.C. Bernotas).
Present address: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington,
DE 19850, USA.
3 WAY-252623
Figure 1. LXR agonists.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.099

J. M. Travins et al. / Bioorg. Med. Chem. Lett. 20 (2010) 526–530
527
fused bicyclic system. We describe here the synthesis and LXR
activity of a series of benzimidazoles 6.
O
Y
SO2R1
O
R2
SO2R1
Preparation of biarylethers 6 generally relied on the synthesis of
core phenols 11 which were either coupled with bromo- or iodoa-
rylsulfones 7, or reacted with fluoro- or chloroarylsulfones 7 in a
displacement reaction. Noncommercial arylsulfones 7 were typi-
cally made by three methods (Scheme 1) to provide a diverse set
of compounds. Partial reduction of an arylsulfonyl chloride with
sodium bisulfite followed by alkylation in the same pot gave 7.16
Ma’s copper iodide mediated coupling procedure17 was also used
to prepare methylsulfones directly from aryl iodide and bromides.
Alkylation of thiophenols followed by oxidation, usually with Ox-
oneÒ, also provided 7.
W
N
N
Y
W
N
Z
Z
5
6
Figure 2. Modifications of 4-[3-(ArO)-Ph]quinolines 5 to 1-[3-(ArO)-Ph]benzimi-
dazoles 6.
SO2R1
X
a (X = SO2Cl) or
Hal
Hal
1-(3-Hydroxyphenyl)-benzimidazoles 11 were synthesized by
several complementary approaches. The first started with a litera-
ture nitration of N-acetyl-3-trifluoromethylaniline to afford a mix-
ture of regioisomers, from which minor desired isomer 8 was
isolated (Scheme 2).18 Nitro reduction followed by heating with
acetic acid gave benzimidazole 9a.19 Coupling20 with iodoanisole
provided 10a which was demethylated to 11a. An alternative ap-
proach to compounds 11 began with deacetylation of 8 to give
nitroaniline 12 which was subjected to a coupling reaction with
an iodoanisole to provide 13 which was in turn reduced to aniline
14. Cyclization of 14 to 10 was accomplished using an acid chloride
followed by treatment with phosphorous oxychloride. Alterna-
tively, reaction of 14 with an orthoester under acidic conditions
gave 10 directly.21 Demethylation of 10 afforded 11 in which both
the R2 and Y groups could be varied. Two approaches were used to
complete the targets from phenols 11 and halogenated arylsulf-
ones 7. Copper-mediated coupling of 11 to an aryl bromide or aryl
iodide, using another Ma procedure,22 afforded biarylethers 6.
Alternatively, biarylether formation could be accomplished by
heating a fluoro or chlorophenylsulfone 7 in the presence of a base.
To efficiently explore the SAR around the 2-position of the benz-
imidazole, a modified route incorporating a biarylether–methyl-
sulfone earlier in the sequence was developed (Scheme 3). 1-
Iodo-3-[3-(methylsulfonyl)phenoxy]benzene (15)23 was coupled
to aniline 12 to afford 16. The nitro group was reduced to give
17. Benzimidazoles 6 were formed by treatment of 17 with an
appropriate acid chloride. More simply, reaction of 17 with an
orthoester in the presence of benzenesulfonic acid gave benzimid-
b (X = Br or I) or
c (X = SH)
W
W
7
Scheme 1. Reagents and conditions: (a) Na2SO3 (1.87 equiv), NaHCO3 (2 equiv),
H2O, 95–100 °C, 1 h, then tetrabutylammonium bromide (catalytic), R1–Br or R1–I
(3–5 equiv), 35–90 °C; (b) NaSO2Me (1.2 equiv), CuI (0.1 equiv),
L-proline
(0.2 equiv), NaOH (0.2 equiv), DMSO, 95 °C, 18 h; (c) R1–Br or R1-I (1.3–1.5 equiv),
K2CO3 (1.5–2 equiv), acetone, 60–70 °C, 2–3 h, then OxoneÒ, aq NaHCO3, rt, 18–
24 h.
Wyeth has also reported a quinoline series incorporating car-
boxylic acid side chains, typified by WAY-254011 (4).11 Quinoline
4 was a high affinity LXRa and LXRb ligand with potent LXR agonist
activity. Unfortunately, 4 was a moderate PPAR agonist, activating
all three subtypes of the receptor.12 Modification of the benzylace-
tic acid group by incorporating other hydrogen bond acceptors and
moving from a benzylic interaryl linker to an oxygen linker while
retaining a 4-phenyl-quinoline core led to series of biarylether
amides,13 alcohols,14 and sulfones15 which gave high affinity LXR
agonists. Sulfones 5 were especially potent in functional assays
with good stability in liver microsomal incubations (Fig. 2). We
turned to explorations of other replacements for the indazole and
quinoline heterocycles in 3 and 5, respectively, to understand the
SAR of the series. Previous reports identified a histidine residue
in the LXRb protein that formed a key interaction with the N1
sp2 nitrogen in both the indazole and quinoline. This suggested
to us that a benzimidazole with a similarly positioned sp2 nitrogen
might be a good choice especially since, like indazole, it is a 5,6-
OMe
OH
H
NHAc
NO2
N
N
N
N
N
a, b
c
d
Me
Me
Me
N
CF3
9a
CF3
CF3
CF3
8
10a
11a
g
e or f
OMe
OMe
OMe
O
SO2R1
R2
R2
R2
NH2
NO2
R2
NH
R3
N
N
N
N
I
i or j
d, then
e or f
Y
Y
W
h
CF3
CF3
CF3
CF3
12
13 R3 = NO2
10
6
a
14 R3 = NH2
Scheme 2. Reagents and conditions: (a) Fe (10 equiv), ethanol, aq HCl (catalytic), AcOH, 70 °C, 4 h; (b) AcOH, 100 °C, 4 h (96%); (c) 3-iodoanisole (2 equiv), CuI (0.2 equiv),
N,N0-dimethyl-trans-1,2-cyclohexanediamine (0.4 equiv), Cs2CO3 (2.2 equiv), DMA, 130 °C, 20 h; (d) pyridine hydrochloride (ca. 20 equiv), 200 °C, 0.5–2 h; (e) 7 (Hal = F or Cl,
1.1–1.5 equiv), K2CO3 (2 equiv), DMF or DMA, 110–150 °C, 18–24 h; (f) 7 (Hal = Br or I, 1.5 equiv), CuI (0.2 equiv), Me2NCH2CO2H hydrochloride (0.3 equiv), Cs2CO3 (6 equiv),
1,4-dioxane, 100–110 °C, 16–24 h; (g) 2 M aq NaOH, MeOH, 60 °C, 1 h (100%); (h) Pd2(dba)3 (0.02 equiv), 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl (0.10 equiv),
K2CO3 (1.2 equiv), tBuOH, 80–90 °C, 3 h (R2 = H: 74%); (i) YCOCl (1–3 equiv), i-PrNEt2 (1–3 equiv), THF, 20 °C, 16 h, then POCl3 (1–3 equiv), then 60–65 °C, 2–20 h; (j) YC(O-
alkyl)3, PhSO3H, THF, 50–60 °C.

528
J. M. Travins et al. / Bioorg. Med. Chem. Lett. 20 (2010) 526–530
O
SO2Me
b
Cl
Cl
O
O
SO2Me
a
b
NH2
NO2
NH2
N
H
Y
NH
NO2
16
Z
Z
15
I
20a Z = Cl
20b Z = H
21a Y = Me, Z = Cl
a
21b Y = CH2CHMe2, Z = Cl
21c Y = Me, Z = H
CF3
CF3
12
OMe
O
SO2Me
c or d
O
Cl
N
HN
OMe
c
SO2Me
Y
NH
N
N
Y
N
Y
Z
Z
N
NH2
22a Y = Me, Z = Cl (60%)
10c Y = Me, Z = Cl (66-83%)
10d Y = CH2CHMe2, Z = Cl (61-71%)
10b Y = Me, Z = H (83-91%)
CF3
CF3
22b Y = CH2CHMe2, Z = Cl (78%)
22c Y = Me, Z = H (80%)
17
6
Scheme 5. Reagents and conditions: (a) YC(O)Cl (1.1 equiv), YCO2H (as solvent),
100 °C; or YC(O)Cl (1.1 equiv), pTsOH hydrate, toluene, reflux, 2 h; (b) 2,6-lutidine
(2.2 equiv, or 3.3 equiv for aniline hydrochlorides), (CF3SO2)2O (1.1 equiv), 0–20 °C,
30–45 min, then aniline, 20 °C, 3–18 h; (c) K2CO3 (1.6 equiv), NaOtBu (1.6 equiv),
Pd(PPh3)4 (0.01–0.15 equiv), toluene, xylenes or DMF, 110–130 °C, 18–32 h.
Scheme 3. Reagents and conditions: (a) 15 (0.8 equiv), Pd2(dba)3 (0.005 equiv),
K2CO3 (1.1 equiv), 2,4,6-triisopropylbiphenyl-dicyclohexylphosphine (0.025 equiv),
tBuOH, 90 °C, 3 h, (80%); (b) Fe (10 equiv), AcOH, 2 N aq HCl, ethanol, 70 °C, 45 min
(98%); (c) YCOCl (1–3 equiv), i-PrNEt2, THF, 20 °C, 16 h, then POCl3 (2–4 equiv), 60–
65 °C. 2–20 h; (d) YC(O-alkyl)3 (excess), PhSO3H (catalytic), THF or CHCl3, 50–60 °C,
20–60 min (Y = Me, 74%).
to 83% using 8% catalyst). To improve the cyclization conditions,
a small study using a simpler substrate (22c) was undertaken (Ta-
ble 1). Using DMF as solvent at 80 °C and 5 mol % Pd(PPh3)4 gave a
poor yield of 10b but the yield improved dramatically at 130 °C.31
Returning to a nonpolar solvent for ease of workup, xylenes at
130 °C also gave similar results. Reducing catalyst loadings down
to 1 mol % provided comparable yields but no product formed in
the absence of catalyst. Applying these conditions to more complex
substrates 22 gave typically good yields, though somewhat higher
catalyst loadings (P2 mol %) were often used. Demethylation and
installation of the arylsulfones as before gave 6. This synthetic
route was very versatile since key positions R1, R2, W, Y and Z could
be varied depending on the choice of reagents.
azole. Moving the diversity step to the end of the route allowed the
Y group SAR to be examined quickly.
Attempts to extend the above approach to compounds 10
where Z is chlorine by coupling 3-iodoanisole to 3-chloro-2-nitro-
aniline gave complex mixtures. At least some of the by-products
apparently arose from coupling of the aniline to another molecule
of aniline via the nitro-activated chlorine, effectively competing
with the iodoanisole. To overcome this issue, chloro analogs were
made by converting aniline 18 into amidines 1924 which were
readily cyclized to benzimidazoles 9 (Z = Cl) using iodosobenzene
acetate25 or sodium hypochlorite26 (Scheme 4). Copper(II)-medi-
ated coupling27 of 9 with 3-methoxyphenylboronic acid afforded
10 which was converted to targets 6 as described above. However,
the coupling step was capricious and often low yielding making
this route suboptimal.
An alternative and more reliable approach to 10 was based on
Brain and Brunton’s28 report of a Pd-catalyzed intramolecular cou-
pling of an N-(2-bromophenyl)-N0-aryl-amidine to give 1-arylbenz-
imidazoles. The commercial availability of anilines 20 led us to try
the coupling using chloro analogs (Scheme 5). Compounds 20 were
converted to acetamides 21.29 Treatment of 21 with trifluorometh-
anesulfonic anhydride and 2,6-lutidine followed by an anisidine
gave amidines 22.30 However, cyclization of 22 under the condi-
tions of Brain and Brunton (PhMe, 80 °C, 5 to 10 mol % Pd(PPh3)4)
gave low yields of 10. At reflux, better yields were obtained (up
Binding affinities for sulfones 6 were determined using recom-
binant human ligand binding domains (LBDs) of the respective
LXRa
and LXRb subtypes measuring displacement of
[3H]T0901317 from the LBD (Table 2).32 Comparing quinoline 5a
to benzimidazole 6a, there was a sevenfold loss in LXRb affinity
and a slightly larger decrease for LXRa. As in other series we have
developed, similar LXR binding affinity was seen whether the Z
group was trifluoromethyl or chlorine (compare 6a to 6b, 6d to
6e, 6f to 6g) but if Z was hydrogen, over a 35-fold drop in affinity
was observed for both LXR subtypes (6a vs 6c). Variations in the
sulfone group from methyl (6a) to ethyl (6d), to isopropyl (6f)
had little effect on affinity but longer chains such as n-propyl
(6h) and 3-hydropropyl (6i) or larger and more electron withdraw-
Table 1
NH
a
b or c
Conditions for cyclization of 22c to 10b
OMe
N
H
Y
NH2
Cl
Cl
Cl
HN
OMe
N
18
19 Y = Me, 2-Pr
Me
N
N
Me
OMe
22c
Solvent
10b
H
N
N
N
Entry
Tempa (°C)
Pd(PPh3)4 (mol %)
Yield of 10bb (%)
d
Y
Y
1
2
3
4
5
6
7
DMF
DMF
80
130
130
130
130
130
130
5
5
5
3
2
1
0
16
88
91
88
83
87
0
N
Cl
9 Y = Me, 2-Pr
Cl
10 Y = Me, 2-Pr
Xylenes
Xylenes
Xylenes
Xylenes
DMF
Scheme 4. Reagents and conditions: (a) Me3Al (1.5 equiv), toluene, 0–20 °C, 1–2 h,
then Y–CN (2 equiv), 85–110 °C, 16–24 h (72–75%); (b) Y = 2-Pr: PhI(OAc)2
(1 equiv), PhMe, reflux, 8–10 min, (54%); (c) aq 2 M HCl, MeOH, 5% aq NaOCl,
10 °C, then aq Na2CO3 (2 equiv), 75 °C (96%); (d) 3-MeOPhB(OH)2 (1.67 equiv),
Cu(OAc)2 (1 equiv), pyridine (3 equiv), CH2Cl2, 4 Å mol sieves, 2–5 d (Y = 2-Pr: 51%).
a
Reaction time was 24 h.
Yield is of isolated product.
b

J. M. Travins et al. / Bioorg. Med. Chem. Lett. 20 (2010) 526–530
529
Table 2
Biarylether sulfone benzimidazoles 6a
O
SO2R1
R2
Z
W
N
N
Y
2
4
R1
R2
W
Y
Z
LXRb IC50
(nM)
LXR
(nM)
a
IC50
IC50
b
a/
ABCA1 mRNA EC50 in
nM (% eff)
TG accum EC50 in
nM (% eff)
Microsome stability t1/2
(min) (m/r/h)
b
1
—
—
—
H
H
H
H
H
H
H
H
—
H
H
H
H
H
H
H
H
H
—
—
9
1.0
7.0
7.3
269
5.7
5.1
5.4
5.6
13
2.4
1
2
35 (100)
10 (82)
425 (126)
270 (165)
ntc
357 (109)
753 (108)
280 (108)
1310 (135)
1330 (105)
Me
104 (100)
147 (69)
271 (37)
124 (31)
nt
262 (42)
220 (32)
179 (34)
134 (22)
273 (27)
CF3
—
5a
6a
6b
6c
6d
6e
6f
6g
6h
6i
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
CF3
CF3
Cl
H
CF3
Cl
CF3
Cl
CF3
30/30/30
30/30/30
30/30/30
nt/15/nt
30/30/30
28/28/30
30/30/30
22/25/30
23/14/28
13
111
100
6400
128
99
248
138
462
H
16
14
17
22
19
46
25
19
H
Et
2-Pr
2-Pr
1-Pr
24
(CH2)3OH
(35)
436
1380
(108)
Me
Me
Me
H
CF3
Et
2-Pr
cyclo-Pr
594
28/25/30
33
6j
6k
6l
6m
6n
6o
6p
6q
6r
CF3
Me
Et
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
10
H
F
F
H
H
H
H
H
H
Cl
20
13
38
44
1.3
1.7
1.0
4.2
183
315
489
882
5.1
22
9
24
13
20
4
13
16
22
1300 (130)
1067 (117)
1270 (119)
841 (84)
14 (94)
122 (8)
192 (33)
168 (34)
524 (35)
185 (49)
120 (42)
212 (53)
907 (66)
CF3
30/30/29
30/30/30
30/30/30
30/30/30
30/30/30
30/30/30
30/30/30
30/30/23
0.8
CF3
CF3
CF3
CF3
CF3
CF3
CF3
78 (90)
16
93
137 (80)
439 (95)
CH2CHMe2
3.2
(92)
76
(127)
3/24/30
4
6s
6t
Me
Me
H
H
H
H
Ph
4-
CF3
CF3
1.1
1.2
4.7
2.6
4
2
333 (65)
nt
2286 (94)
nt
16/30/11
8/30/23
FPhCH2
2-Pr
H
H
H
Me
Me
Me
Me
Me
6u
6v
6w
6x
6y
Me
Me
Et
2-Pr
Me
Et
2-Pr
Me
CF3
H
H
H
H
H
H
H
H
F
Cl
1.5
2.7
2.4
4.0
3.7
3.5
3.6
4.7
17
26
34
35
45
14
12
36
44
85
17
14
15
11
4
3
10
9
156 (97)
425 (104)
155 (122)
240 (100)
154 (78)
245 (126)
110 (99)
215 (110)
620 (117)
617 (91)
218 (45)
197 (35)
205 (28)
50 (90)
184 (35)
298 (43)
297 (57)
879 (38)
9/7/30
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CF3
CF3
CF3
Cl
Cl
Cl
30/nt/30
30/nt/30
27/nt/30
26/nt/30
20/22/30
11/15/25
16/30/30
30/30/30
6z
6aa
6bb
6cc
Cl
Cl
H
5
a
Results are given as the mean of two independent experiments. The standard deviations for the binding assays were typically 30% of the mean or less. % of efficacy is
relative to 1.
b
m = mouse, r = rat, h = human; t1/2 of 30 min means indicates a half-life of P30 min.
nt = not tested.
c
ing groups (trifluoromethyl, 6j) tended to reduce affinity. Fluorine
substitution on the sulfone-bearing aryl ring (6k, 6l, 6bb) either re-
duced affinity or had little effect. Decreasing the size of the 2-sub-
stituent Y to hydrogen (6m) reduced affinity at least sixfold while
improved affinity was found as Y was increased in size (6n–6t).
However, even 6n (Y = CF3) gave improved affinity, indicating lar-
ger groups like phenyl (6s) and 4-fluorobenzyl (6t) disproportion-
ately increased size relative to affinity increases. Introduction of a
chloro group at R2, which was proposed from docking studies to
compensate for a small group (hydrogen) at the 2-position, did im-
prove LXRb affinity about 15-fold (compare 6m to 6v) but had less
impact on binding for compounds where Y was methyl (6b vs 6y).
pounds tested had any significant PPARa, PPARd, or PPARc agon-
ism in transiently transfected cell lines previously described.13
Compounds 6 were further tested for increases in ABCA1 mRNA
in a THP1 (human macrophage) cell line32 and for changes in cel-
lular triglyceride (TG) levels in an HepG2 (human liver) cell line
(Table 2).12 Increases in the ABCA1 levels should correlate to lipid
efflux from macrophages, a desired effect in the treatment of ath-
erosclerosis while increases in cellular TG concentrations could re-
late to the undesired accumulation of lipids, especially in the liver,
leading to steatosis. Efficacy in both assays was measured relative
to 1 with the maximum increase in mRNA and in TG levels taken as
100% efficacy. Comparing quinoline 5a to benzimidazole 6a, the
latter had an EC50 over 40-fold weaker in the ABCA1 assay. Despite
the high binding affinity and though they typically had efficacies
comparable to 1, most of the benzimidazoles 6 had EC50 values
>100 nM in the assay. The exceptions (6n, 6o, and 6r) had Y groups
that were slightly larger than methyl, though much larger Y groups
(6s, Y = Ph) reduced activity. Efficacies for the benzimidazoles in
the triglyceride accumulation assay were generally lower than
for 1, but only 6n and 6r showed significantly higher potency in
Binding selectivity for LXRb over LXRa subtypes was moderate
to good (typically 10–25-fold) with one analog (6f) approaching
50-fold selectivity. Generally, the level of LXRb binding selectivity
was higher for the benzimidazoles 6 than for quinolines 5. LXRb
agonist functional selectivity may have advantages in increasing
cholesterol efflux without increases in triglyceride levels seen with
nonselective LXR agonists33 though others have suggested LXR
a
agonism is a better therapeutic target.34 Finally, none of the com-

530
J. M. Travins et al. / Bioorg. Med. Chem. Lett. 20 (2010) 526–530
Table 3
Li Di, Ronald Magolda (deceased June 1, 2008), Steven Gardell,
and George Vlasuk.
Mouse PK for compounds 6a
O
SO2R1
References and notes
N
N
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Y
Z
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R1
Y
Z
AUC0–last ng h/mL
t1/2 (h)
6a
6b
6d
6e
6f
6m
6n
6o
Me
Me
Et
Me
Me
Me
Me
Me
H
CF3
Cl
CF3
Cl
CF3
CF3
CF3
CF3
12,917
1499
2944
1776
1291
12,148
14,338
1781
13.5
1.7
4.7
3.6
0.9
7.9
ncb
2.7
Et
2-Pr
Me
Me
Me
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CF3
Et
9. Wrobel, J.; Steffan, R.; Bowen, S. M.; Magolda, R.; Matelan, E.; Unwalla, R.;
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a
C57 mouse dosing: 10 mg/kg po (gavage) in 0.5% methylcellulose/2% Tween in
water.
b
Not calculated—a longer study time was needed to determine t1/2
.
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the ABCA1 assay compared to the TG accumulation assay. The rel-
evance of this level of selectivity is not clear given the different cell
types and potentially differing cell penetration by the drugs.
In an assay testing for in vitro metabolic stability in mouse, rat
and human microsomes, most of the compounds had good stability
as measured by the half-life. Typically, as noted above, compounds
with larger alkyl groups and benzyl substitution at Y appeared
more susceptible to microsomal metabolism (6r–6t). 4-Chloro
benzimidazoles were occasionally slightly less stable compared
to their trifluoromethyl analogs. Since the majority of the com-
pounds were stable in vitro, several compounds were tested to
15. Bernotas, R. C.; Singhaus, R. R.; Kaufman, D. H.; Travins, J. T.; Ullrich, J. W.;
Unwalla, R. J.; Quinet, E.; Evans, M.; Nambi, P.; Olland, A.; Kauppi, B.;
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16. New compounds gave satisfactory 1H NMR, MS, and HRMS data and were
generally >95% pure by HPLC analysis. For experimental details, see
WO2008049047 for arylsulfones 7 and WO2009086138 for benzimidazole
syntheses.
10 mg/kg oral (gavage) dose in mice (Table 3). Compounds where
the Z-substituent was trifluoromethyl had higher exposure and
longer half-life compared to their chlorine analogs (compare 6a
to 6b, 6d to 6e) while when the Y-substituent was ethyl (6o), the
pharmacokinetic (PK) parameters were less favorable compared
to when Y was hydrogen (6m), methyl (6a) or trifluoromethyl
(6n). The compound with the shortest half-life (6f) had an isopro-
pyl group for R1 which might be more readily metabolized.
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oromethylbenzimidazole core while retaining a sulfone-substi-
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human macrophage cell line (THP1) showed increases in mRNA
for ABCA1, a key protein involved in lipid transport. In this assay,
the potency and efficacy were often comparable to 1, with a few
compounds having even higher potency. Unfortunately, a second
functional assay measuring increases in TG levels in a human hepa-
tic cell line (HepG2) indicated the most potent compounds for
increasing desired ABCA1 mRNA levels also increased intracellular
TG levels. Stability in mouse and human liver microsomes was high
for the majority of analogs 6. 1-(3-Aryloxyaryl)benzimidazoles
with a meta-sulfone group on the distal phenyl ring are high affin-
ity LXR ligands, often with excellent agonist potency for upregulat-
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Acknowledgments
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We thank Wyeth Discovery Analytical Chemistry for analytical
data and Anita Halpern and Dawn Savio for biological data. We
acknowledge the support of Drs. Mark Evans, Rayomand Unwalla,